The long-term broad objectives of this research are to develop reversible antagonists that are selective for specific opioid receptor types and subtypes. Ideally, these ligands should be relatively stable to metabolic inactivation, be able to penetrate the blood-brain barrier, and have high affinity and potency for the target sites. We will employ such ligands as tools to sort out the physiologic and pharmacologic effects produced by endogenous or exogenous opioids. Two classes of bivalent ligands will be synthesized. The first class contains two naltrexone-derived pharmacophores, the second class is characterized by a single antagonist pharmacophore (the "message") joined to a non-pharmacophore recognition unit designated as the "address" (a portion of the ligand that confers subtype selectivity). A key feature of both bivalent ligand classes that is expected to play an important role in conferring selectivity is the presence of rigid spacers that connect the recognition units. In the dimeric bivalent ligands, the geometry and length of the rigid spacers will be varied in order to investigate the relationship between the orientation of the rigidly held pharmacophores and opioid antagonist selectivity. These structure-selectivity studies have been designed to provide us with insight into the mode of interaction of such ligands with different opioid receptor types. When such studies suggest that simultaneous occupation of the "message" and "address" subsites of a single opioid receptor by a ligand is involved, one of the phamacophores of the dimer will be replaced with the key address moieties that confer selectivity. Such ligands represent the second class of bivalent ligands mentioned above. A total number of 43 target compounds have been proposed for synthesis by four different routes. All target compounds will be tested in three smooth muscle preparations and in the opioid receptor binding assay. Selective ligands will be evaluated further in mice using two different antinociceptive assays. Further studies will be conducted on the kappa antagonist nor-BNI and its congeners to determine if they are acting on a single or multiple populations of kappa opioid receptors.